The objectives of this research project have been to determine the cellular sites and molecular mechanisms underlying the effects of chronic Li treatment on the central nervous system. Initial objectives were to identify possible selective actions (acute and chronic) of Li on specific target neurons known to receive synaptic inputs which are already characterized neurochemically. Our results indicate that acute Li selectively antagonizes iontophoretic actions of norepinephrine and of locus coeruleus stimulation on cerebellar Purkinje cells and on hippocampal pyramidal neurons. However, this antagonism does not persist when rats are maintained on therapeutic human plasma levels of Li; with chronic Li treatment of 7-10 days, noradrenergic antagonism disappears and cells become supersensitive to NE in both cerebellum and hippocampus. This change is accompanied by enhancement of norepinephrine-activated adenylate cyclase. We now propose to extend this research by evaluating further the selectivity of the effects of chronic Li treatments on other neurotransmitters in hippocampus (acetylcholine, enkephalins, and serotonin), and in cerebral cortex; and to characterize in more detail the time course of the switch from antagonistic effects on noradrenergic transmission to potentiative effects in cerebellum, hippocampus and other noradrenergic target areas. We will do similar analysis on cells which are primary targets of dopamine and serotonin. We will develop additional in vitro assay systems for more precise description of the molecular mechanisms underlying these effects of Li action. We will locate synaptic sites exhibiting cyclic AMP-dependent protein kinase substrate proteins as one additional test of specificity. Behavioral experiments will be initiated to develop model systems which will simulate the manic state in order to determine if the effects observed here in normal animals could cause the possible therapeutic effects Li. These experiments can provide insight into the mechanisms by which Li the mental status of subjects with manic-depressive psychosis and may provide better methods for diagnosis, treatment and prevention of this illness.